Immune-mediated diseases appear to be increasing in prevalence in the population. These disorders are thought to be the result of chronic lymphocyte activation by selected environmental exposures in genetically susceptible individuals. The reasons for these reported increases in immune mediated diseases are unclear, although our increasing exposure to novel immune-altering biologics, foods, drugs, and devices may play a role in this phenomenon. We are investigating the pathogenesis, and environmental/genetic risk factors, that lead to these diseases that result in high morbidity and mortality. Specific investigations underway include: A. Immunogenetic risk factors for, and pathogenesis of, selected connective tissue and autoimmune diseases that develop following exposure to biologics (including vaccines), drugs, foods, and medical devices. Sera and cell banks and large databases of clinical and genetic data, are being developed from idiopathic myositis patients, adult and pediatric to compare the environmentally-related cases to this population and to gain an understanding of the natural history and disease assessment of these disorders. Preliminary data suggest that the myositis that develops after silicone implants differs from idiopathic myositis in clinical features, serology, immunogenetics, and target organ T cell receptor (TCR) use. Preliminary studies of the capsules surrounding explanted silicone mammary prostheses suggest that ongoing immune responses to silicone involve activation of macrophages, B cells and T lymphocytes via selected TCR utilization. Preliminary animal studies suggest that the type and route of silicone administration greatly alters local and systemic immune responses and pathology. B. Pathogenesis of silicone-associated B lymphocyte activation. Silicone associated multiple myeloma (S-MM) and monoclonal gammopathy of undetermined significance (S-MGUS) are currently under investigation. As a result of our finding that some silicones induce plasmacytomas in genetically susceptible mice, we are evaluating the clinical features, immune responses and immunogenetics of S-MM and S-MGUS. Two multi-center case-controlled studies are underway comparing either S-MM or S-MGUS patients with matched silicone controls and idiopathic MM or MGUS patients. C. Genetic risk factors for development of L-tryptophan-induced eosinophilia myalgia syndrome (EMS) are being studied. Preliminary data from case controlled exposure studies suggest that HLA DRB1 alleles determine risk for development of EMS and many of its sequelae. These studies have important implications in that immune-mediated adverse events to biologics, foods, drugs and devices are frequently the limiting factor in the development of novel therapies and vaccines. Better definition of genetic risk factors for these adverse events understanding their mechanisms could lead to appropriate screening of populations that could prevent or minimize these adverse events.